Effects of a low-pressure hyperbaric oxygen therapy on psychological constructs related to pain and quality of life in women with fibromyalgia: A randomized clinical trial.

BACKGROUND AND OBJECTIVES: Self-reported psychological variables related to pain have been posited as the major contributors to the quality of life of fibromyalgia (FM) women and should be considered when implementing therapeutic strategies among this population. The aim of this study was to explore the effect of low-pressure hyperbaric oxygen therapy (HBOT) on psychological constructs related to pain (i.e., pain catastrophism, pain acceptance, pain inflexibility, mental defeat) and quality of life in women with FM. METHODS: This was a randomized controlled trial. Thirty-three women with FM were randomly allocated to a low-pressure hyperbaric oxygen therapy group (HBOTG) (n=17), who received an 8-week intervention (5 sessions per week), and a control group (CG) (n=16). All women were assessed at baseline (T0) and upon completion of the study (T1) for self-perceived pain intensity, pain catastrophism, pain acceptance, pain inflexibility, mental defeat and quality of life. RESULTS: At T1, the HBOTG improved across all variables related to pain (i.e. self-perceived pain intensity, pain catastrophism, pain acceptance, pain flexibility, mental defeat) (p<0.05) and quality of life (p<0.05). In contrast, the CG showed no improvements in any variable. Furthermore, significant differences between the groups were found in quality of life (p<0.05) after the intervention. CONCLUSIONS: HBOT is effective at improving the psychological constructs related to pain (i.e. pain catastrophism, pain acceptance, pain flexibility, mental defeat) and quality of life among women with FM. Clinical Trial Link Clinical Trials gov identifier (NCT03801109).

Pharmacological Properties of Polyphenols: Bioavailability, Mechanisms of Action, and Biological Effects in In Vitro Studies, Animal Models, and Humans.

Drugs are bioactive compounds originally discovered from chemical structures present in both the plant and animal kingdoms. These have the ability to interact with molecules found in our body, blocking them, activating them, or increasing or decreasing their levels. Their actions have allowed us to cure diseases and improve our state of health, which has led us to increase the longevity of our species. Among the molecules with pharmacological activity produced by plants are the polyphenols. These, due to their molecular structure, as drugs, also have the ability to interact with molecules in our body, presenting various pharmacological properties. In addition, these compounds are found in multiple foods in our diet. In this review, we focused on discussing the bioavailability of these compounds when we ingested them through diet and the specific mechanisms of action of polyphenols, focusing on studies carried out in vitro, in animals and in humans over the last five years. Knowing which foods have these pharmacological activities could allow us to prevent and aid as concomitant treatment against various pathologies.

Effectiveness of High-Frequency Transcranial Magnetic Stimulation and Physical Exercise in Women With Fibromyalgia: A Randomized Controlled Trial.

OBJECTIVE: Fibromyalgia (FM) is characterized by chronic widespread pain and both physical and emotional alterations, which in turn may affect the individual's quality of life. Thus, interventions aimed at treating such symptoms, without increasing fatigue, are needed. The aim of this study was to explore the effect of high-frequency transcranial magnetic stimulation (HF-TMS) and physical exercise (PE) on pain, impact of FM, physical conditioning, and emotional status in women with FM. METHODS: Forty-nine women with FM were randomly allocated to: (1) a PE group (PEG, n = 16), who underwent an 8-week (two 60-minute sessions/wk) low-intensity PE program; (2) a TMS group (TMSG, n = 17) receiving a 2-week (five 20-minute sessions/wk) HF-TMS intervention; and (3) a control group (CG, n = 16). Pain (ie, perceived pain and average pressure pain threshold), perceived impact of FM (ie, overall impact, symptoms, and perceived physical function), physical conditioning (ie, endurance and functional capacity, fatigue, gait velocity, and power), and emotional status (ie, anxiety, depression, stress, and satisfaction) were assessed at baseline (T0) and after the intervention (T1, at 2 weeks for TMSG and at 8 weeks for PEG and CG). RESULTS: The TMSG showed significant improvement in all studied variables after the intervention except for satisfaction, whereas the PEG showed improved average pressure pain threshold, perceived overall impact of FM and total score, endurance and functional capacity, velocity and power, anxiety, depression, and stress. In contrast, the CG showed no improvements in any variable. CONCLUSION: Both PE and HF-TMS are effective in improving pain, impact of FM, physical conditioning, and emotional status in people with FM; HF-TMS achieved larger improvements in emotional status than PE. IMPACT: TMS and PE have similar benefits for physical status, whereas TMS has greater benefits than PE for emotional status in women with FM.

Moderate Red Wine Consumption Increases the Expression of Longevity-Associated Genes in Controlled Human Populations and Extends Lifespan in Drosophila melanogaster.

The beneficial effects of moderate red wine consumption on cardiovascular health are well known. The composition of red wine includes several compounds, such as the phytoestrogen resveratrol, that exert these beneficial effects, although not all the mechanisms by which they act are known. Our aim was to study the effect of red wine consumption on longevity-related genes in controlled human populations, such as cloistered nuns. We found that the expression of catalase, manganese-superoxide dismutase, Sirt1, and p53 was increased in peripheral blood mononuclear cells after 14 days of moderate red wine consumption. This increase was accompanied by an enhanced metabolic wellness: fatty acids, cholesterol, branched chain amino acids (isoleucine and leucine), ketone bodies (acetoacetate), bacterial co-metabolites (trimethylamine), and cellular antioxidants (taurine) contributed to a change in metabolic profile after moderate red wine consumption by the nuns. No serious unwanted side effects were observed. Finally, we tested the effect of moderate red wine consumption on longevity in a controlled animal population, such as D. melanogaster, and found that it increased average life span by 7%. In conclusion, moderate red wine consumption increases the expression of key longevity-related genes and improves metabolic health in humans and increases longevity in flies.

Relationship between Diet, Microbiota, and Healthy Aging.

Due to medical advances and lifestyle changes, population life expectancy has increased. For this reason, it is important to achieve healthy aging by reducing the risk factors causing damage and pathologies associated with age. Through nutrition, one of the pillars of health, we are able to modify these factors through modulation of the intestinal microbiota. The Mediterranean and Oriental diets are proof of this, as well as the components present in them, such as fiber and polyphenols. These generate beneficial effects on the body thanks, in part, to their interaction with intestinal bacteria. Likewise, the low consumption of products with high fat content favors the state of the microbiota, contributing to the maintenance of good health.

Comparative study of the effectiveness of a low-pressure hyperbaric oxygen treatment and physical exercise in women with fibromyalgia: randomized clinical trial.

BACKGROUND: Fibromyalgia (FM) is characterized by chronic pain and fatigue, among other manifestations, thus advising interventions that do not aggravate these symptoms. The main purpose of this study is to analyse the effect of low-pressure hyperbaric oxygen therapy (HBOT) on induced fatigue, pain, endurance and functional capacity, physical performance and cortical excitability when compared with a physical exercise program in women with FM. METHODS: A total of 49 women with FM took part in this randomized controlled trial. They were randomly allocated to three groups: physical exercise group (PEG, n = 16), low-pressure hyperbaric oxygen therapy group (HBG, n = 17) and control group (CG, n = 16). Induced fatigue, perceived pain, pressure pain threshold, endurance and functional capacity, physical performance and cortical excitability were assessed. To analyse the effect of the interventions, two assessments, that is, pre and post intervention, were carried out. Analyses of the data were performed using two-way mixed multivariate analysis of variance. RESULTS: The perceived pain and induced fatigue significantly improved only in the HBG (p < 0.05) as opposed to PEG and CG. Pressure pain threshold, endurance and functional capacity, and physical performance significantly improved for both interventions (p < 0.05). The cortical excitability (measured with the resting motor threshold) did not improve in any of the treatments (p > 0.05). CONCLUSIONS: Low-pressure HBOT and physical exercise improve pressure pain threshold, endurance and functional capacity, as well as physical performance. Induced fatigue and perceived pain at rest significantly improved only with low-pressure HBOT. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03801109.

Extracellular Vesicles from Healthy Cells Improves Cell Function and Stemness in Premature Senescent Stem Cells by miR-302b and HIF-1α Activation.

Aging is accompanied by the accumulation of senescent cells that alter intercellular communication, thereby impairing tissue homeostasis and reducing organ regenerative potential. Recently, the administration of mesenchymal stem cells (MSC)-derived extracellular vesicles has proven to be more effective and less challenging than current stem cell-based therapies. Extracellular vesicles (EVs) contain a cell-specific cargo of proteins, lipids and nucleic acids that are released and taken up by probably all cell types, thereby inducing functional changes via the horizontal transfer of their cargo. Here, we describe the beneficial properties of extracellular vesicles derived from non-senescent MSC, cultured in a low physiological oxygen tension (3%) microenvironment into prematurely senescent MSC, cultured in a hyperoxic ambient (usual oxygen culture conditions, i.e., 21%). We observed that senescent MCS, treated with EVs from non-senescent MCS, showed reduced SA-ß-galactosidase activity levels and pluripotency factor (OCT4, SOX2, KLF4 and cMYC, or OSKM) overexpression and increased glycolysis, as well as reduced oxidative phosphorylation (OXPHOS). Moreover, these EVs' cargo induced the upregulation of miR-302b and HIF-1α levels in the target cells. We propose that miR-302b triggered HIF-1α upregulation, which in turn activated different pathways to delay premature senescence, improve stemness and switch energetic metabolism towards glycolysis. Taken together, we suggest that EVs could be a powerful tool to restore altered intercellular communication and improve stem cell function and stemness, thus delaying stem cell exhaustion in aging.

The Relationship between Diet and Frailty in Aging.

The increase in lifespan in the 20th century entails an increase in the elderly population. This brings a new challenge for society, causing people to have physical and mental limitations caused by age-related diseases, such as frailty. Frailty is clinically characterized by multisystem pathophysiological processes, such as chronic inflammation, immune activation, dysregulation of the musculoskeletal and endocrine systems, oxidative stress, energy imbalances, mitochondrial dysfunction, and sarcopenia. The elderly should consume energy in amounts close to those in what is currently accepted as a balanced diet. However, an increase in protein intake may be recommended for elderly people as long as there is no kidney damage. This increase could help fight the loss of muscle mass associated with age. Additionally, vitamin and mineral intakes are often insufficient in their diets. Therefore, the diet should be adapted not only to their age, but also to the pathologies associated with aging. Through these measures, we can reduce the prevalence of comorbidity and thereby increase health span. Therefore, both physical and nutritional interventions, including functional foods and nutraceuticals, should be taken into account.

Low-Intensity Physical Exercise Improves Pain Catastrophizing and Other Psychological and Physical Aspects in Women with Fibromyalgia: A Randomized Controlled Trial.

Fibromyalgia (FM) is a chronic syndrome characterized by widespread pain and other physical and psychological features. In this study, we aimed to analyze the effect of a low-intensity physical exercise (PE) program, combining endurance training and coordination, on psychological aspects (i.e., pain catastrophizing, anxiety, depression, stress), pain perception (i.e., pain acceptance, pressure pain threshold (PPT), and quality of life and physical conditioning (i.e., self-perceived functional capacity, endurance and functional capacity, power and velocity) in women with FM. For this purpose, a randomized controlled trial was carried out. Thirty-two women with FM were randomly allocated to a PE group (PEG, n = 16), performing an eight-week low-intensity PE program and a control group (CG, n = 16). Pain catastrophizing, anxiety, depression, stress, pain acceptance, PPT, quality of life, self-perceived functional capacity, endurance and functional capacity, power, and velocity were assessed before and after the intervention. We observed a significant improvement in all studied variables in the PEG after the intervention (p < 0.05). In contrast, the CG showed no improvements in any variable, which further displayed poorer values for PPT (p < 0.05). In conclusion, a low-intensity combined PE program, including endurance training and coordination, improves psychological variables, pain perception, quality of life, and physical conditioning in women with FM.

BCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians.

B-Cell Lymphoma-extra-large (BCL-xL) is involved in longevity and successful aging, which indicates a role for BCL-xL in cell survival pathway regulation. Beyond its well described role as an inhibitor of apoptosis by preventing cytochrome c release, BCL-xL has also been related, indirectly, to autophagy and senescence pathways. Although in these latter cases, BCL-xL has dual roles, either activating or inhibiting, depending on the cell type and the specific conditions. Taken together, all these findings suggest a precise mechanism of action for BCL-xL, able to regulate the crosstalk between apoptosis, autophagy, and senescence, thus promoting cell survival or cell death. All three pathways can be both beneficial or detrimental depending on the circumstances. Thus, targeting BCL-xL would in turn be a "double-edge sword" and therefore, additional studies are needed to better comprehend this dual and apparently contradictory role of BCL-XL in longevity.

Extracellular vesicles and redox modulation in aging.

Extracellular vesicles (EVs) are nowadays known to be mediators of cell-to-cell communication involved in physiological and pathological processes. The current expectation is their use as specific biomarkers and therapeutic tools due to their inner characteristics. However, several investigations still need to be done before we can use them in the clinic. First, their categorization is still under debate, although an accurate classification of EVs subtypes should be based on physical characteristics, biochemical composition or condition description of the cell of origin. Second, EVs carry lipids, proteins and nucleic acids that can induce epigenetic modifications on target cells. These cargos, as well as EVs biogenesis, shedding and uptake is both ageing and redox sensitive. More specifically, senescence and oxidative stress increase EVs release, and their altered content can trigger antioxidant but also prooxidant responses in target cells thereby modulating the redox status. Further analysis would help to asses EVs role in the development and progression of oxidative stress-related pathologies. In this review we aimed to summarize the current knowledge on EVs and their involvement in redox modulation on age-related pathologies. We also discuss future directions and prospective that could be performed to improve EVs usage as biomarkers or therapeutic tools.

Relation Between Genetic Factors and Frailty in Older Adults.

OBJECTIVES: Frailty is a geriatric syndrome that identifies individuals at higher risk of disability, institutionalization, and death. We previously reported that frailty is related to oxidative stress and cognitive impairment-related biomarkers. The aim of this study was to determine whether frailty is associated with genetic variants. DESIGN: Longitudinal population-based cohort of 2488 community-dwelling people from Toledo, Spain, aged 65 years or older. SETTING AND PARTICIPANTS: We obtained blood samples from 78 individuals with frailty and 74 nonfrail individuals who were nonfrail (according to Fried criteria) from the Toledo Study of Healthy Ageing and extracted DNA using the Chemagic DNA blood kit. MEASURES: Sample genotyping was carried out by means of Axiom Exome 319 Genotyping Array (Thermo Fisher Scientific), which contains 295,988 markers [single-nucleotide polymorphisms (SNPs) and rare variants], and transferred to the GeneTitan Instrument (Affymetrix). RESULTS: We found 15 SNPs (P < .001), 18 genes (P < .005), and 4 pathways (P < .05) related to cytokine-cytokine receptor interaction, natural killer cell-mediated cytotoxicity, regulation of autophagy, and renin-angiotensin system as the most strongly associated with frailty. CONCLUSIONS/IMPLICATIONS: The specific genetic features related to energy metabolism, biological processes regulation, cognition, and inflammation highlighted by this preliminary analysis offer useful insights for finding biologically meaningful biomarkers of frailty that allow early diagnosis and treatment. Further research is needed to confirm our novel findings in a larger population. Indeed, the EU-funded FRAILOMICS research effort will address this question.

Relevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine.

The key hallmark of stem cells is their ability to self-renew while keeping a differentiation potential. Intrinsic and extrinsic cell factors may contribute to a decline in these stem cell properties, and this is of the most importance when culturing them. One of these factors is oxygen concentration, which has been closely linked to the maintenance of stemness. The widely used environmental 21% O2 concentration represents a hyperoxic non-physiological condition, which can impair stem cell behaviour by many mechanisms. The goal of this review is to understand these mechanisms underlying the oxygen signalling pathways and their negatively-associated consequences. This may provide a rationale for culturing stem cells under physiological oxygen concentration for stem cell therapy success, in the field of tissue engineering and regenerative medicine.

Hydrogen Peroxide Diffusion through Enamel and Dentin.

The purpose of this study was to evaluate the in vitro diffusion of commercial bleaching products (hydrogen peroxide (HP) or carbamide peroxide (CP) based) with different application protocols. Human enamel-dentin discs were obtained and divided into 20 groups. Four commercial products based on HP (Pola Office+(PO), Perfect Bleach (PB), Norblanc Office-automix (NO), and Boost (BT)), and one based on CP (PolaDay CP (PD)), were evaluated with different application protocols (3 applications × 10 min or 1 application × 30 min, with or without light activation). Artificial pulp chambers with 100 µL of a buffer solution were prepared. After each application, the buffer was removed and diffused HP was quantified by fluorimetry. Data were analyzed with two-way analysis of variance (ANOVA) and Tukey's test. In groups where 3 × 10 min applications were done, after the first 10 min, PB, NO, and PD showed similar diffusion (p < 0.05). After the second and third applications, diffusion proved similar for PO and PD, while PB exhibited the greatest diffusion. In the 30 min application groups, PO and BT showed no significant differences (p > 0.05), with similar results for NO and PD. Comparing products with or without light activation, PO, BT, and PB showed significantly greater diffusion with light activation (p < 0.05). Reapplication, and light activation, increased HP diffusion independently of the concentration of the product.

Identificación de polimorfismos de un solo nucleótido relacionados con la fragilidad / Identification of single nucleotide polymorphisms related to frailty

Introducción: La búsqueda de biomarcadores que permitan la detección y el posible tratamiento precoz de la fragilidad se ha convertido en uno de los objetivos primordiales de la comunidad científica geriátrica. El objetivo del presente estudio fue identificar polimorfismos de un solo nucleótido ([SNP] del inglés single nucleotide polymorphisms) relacionados con la fragilidad. Material y métodos: El estudio se llevó a cabo en 152 sujetos de la cohorte del Estudio de Toledo (de 65 a 95 años de edad), clasificados como frágiles (n=78), y no frágiles (n=74), según los criterios de Fried. Tras la extracción de sangre se aisló y amplificó el ADN para el análisis de SNP mediante la tecnología AxiomTMGenotyping de Affymetrix. Los análisis estadísticos fueron realizados mediante el programa Plink y la biblioteca de R library SNPassoc para Windows. Resultados: Los resultados del análisis mostraron 15 SNP con un valor de p inferior a 0,001. Destacamos aquellos implicados en procesos relacionados con la fragilidad, como el metabolismo energético, la regulación de procesos biológicos, la motilidad e integridad celular y la cognición. Conclusiones: Los resultados sugieren que las variaciones genéticas identificadas en individuos frágiles y que están implicadas en procesos biológicos relacionados con la fragilidad podrían constituir biomarcadores que contribuyan a la detección precoz de la misma

Introduction: The search for biomarkers that can lead to the early diagnosis and thus, early treatment of frailty, has become one of the main challenges facing the geriatric scientific community. The aim of the present study was to identify single nucleotide polymorphisms (SNPs) related to frailty. Material and methods: The study was conducted on 152 subjects from the Toledo Study for Healthy Aging (65 to 95 years of age), and classified as frail (n=78), and non-frail (n=74), according to Fried's criteria. After blood collection, DNA was isolated and amplified for the analysis of SNPs using AxiomTM Genotyping technology (Affymetrix). Statistical analyses were performed using the Plink program and library SNPassoc. Results: The results of the study showed 15 SNPs with a P<.001. Those SNPs involved in processes related to frailty, such as energy metabolism, regulation of biological processes, cell motility and integrity, and cognition are highlighted. Conclusions: These results suggest that the genetic variations identified in frail individuals that are involved in biological processes related to frailty may be considered as biomarkers for the early detection of frailty

[Identification of single nucleotide polymorphisms related to frailty]. / Identificación de polimorfismos de un solo nucleótido relacionados con la fragilidad.

INTRODUCTION: The search for biomarkers that can lead to the early diagnosis and thus, early treatment of frailty, has become one of the main challenges facing the geriatric scientific community. The aim of the present study was to identify single nucleotide polymorphisms (SNPs) related to frailty. MATERIAL AND METHODS: The study was conducted on 152 subjects from the Toledo Study for Healthy Aging (65 to 95 years of age), and classified as frail (n=78), and non-frail (n=74), according to Fried's criteria. After blood collection, DNA was isolated and amplified for the analysis of SNPs using AxiomTM Genotyping technology (Affymetrix). Statistical analyses were performed using the Plink program and library SNPassoc. RESULTS: The results of the study showed 15 SNPs with a P<.001. Those SNPs involved in processes related to frailty, such as energy metabolism, regulation of biological processes, cell motility and integrity, and cognition are highlighted. CONCLUSIONS: These results suggest that the genetic variations identified in frail individuals that are involved in biological processes related to frailty may be considered as biomarkers for the early detection of frailty.

Identificación de polimorfismos de nucleótido simple en centenarios / Identification of single nucleotide polymorphisms in centenarians

Introducción. La longevidad viene determinada por la genética propia de cada especie y por factores externos, tales como nutricionales, ambientales, sociales, etc. Sin embargo, los individuos más longevos se caracterizan por presentar una mayor adaptación al entorno condicionada predominantemente por su propia genética. Dentro de una misma población con relativa homogeneidad genotípica, podemos encontrar cambios sutiles en la secuencia de ADN que afectan únicamente a un nucleótido. Estos cambios denominados polimorfismos de nucleótido simple (Single Nucleotide Polimorphisim [SNP]) se encuentran con una prevalencia mayor al 1-5% de la población. Por ello, nos planteamos estudiar en individuos centenarios si las posibles variaciones genéticas, analizando SNP, podrían tener alguna relevancia en la longevidad extrema que experimentan. Material y métodos. Se reclutó a 92 sujetos: 28 centenarios y 64 controles. Se les extrajo sangre, se aisló y amplificó ADN para el análisis de SNP mediante la tecnología Axiom™ Genotyping de Affymetrix. Los análisis estadísticos se realizaron mediante el programa Plink y varias bibliotecas de R para Windows (library SNPassoc, skatMeta). Resultados. Los resultados del análisis muestran 12 SNP que presentan un valor de p inferior a 0,001, donde 5 de ellos (DACH1, LOC91948, BTB16, NFIL3 y HDAC4) tienen funciones reguladoras de la expresión de otros genes. Conclusiones. Así pues, los resultados sugieren que las variaciones genéticas observadas entre centenarios y controles tienen lugar en 5 genes que están implicados en la regulación de la expresión génica, capacitándolos a adaptarse a diferentes condiciones ambientales con mejor éxito (AU)

Introduction. Longevity is determined by genetic and external factors, such as nutritional, environmental, social, etc. Nevertheless, when living conditions are optimal, longevity is determined by genetic variations between individuals. In a same population, with relative genotypic homogeneity, subtle changes in the DNA sequence affecting a single nucleotide can be observed. These changes, called single nucleotide polymorphisms (SNP) are present in 1-5% of the population. Material and methods. A total of 92 subjects were recruited, including 28 centenarians and 64 controls, in order to find SNP that maybe implicated in the extreme longevity, as in the centenarians. Blood samples were collected to isolate and amplify the DNA in order to perform the analysis of SPN by Axiom™ Genotyping of Affymetrix technology. Statistical analyses were performed using the Plink program and libraries SNPassoc and skatMeta. Results. Our results show 12 mutations with a p<.001, where 5 of these (DACH1, LOC91948, BTB16, NFIL3 y HDAC4) have regulatory functions of the expressions of others genes. Conclusions. Therefore, these results suggest that the genetic variation between centenarians and controls occurs in five genes that are involved in the regulation of gene expression to adapt to environmental changes better than controls (AU)

[Identification of single nucleotide polymorphisms in centenarians]. / Identificación de polimorfismos de nucleótido simple en centenarios.

INTRODUCTION: Longevity is determined by genetic and external factors, such as nutritional, environmental, social, etc. Nevertheless, when living conditions are optimal, longevity is determined by genetic variations between individuals. In a same population, with relative genotypic homogeneity, subtle changes in the DNA sequence affecting a single nucleotide can be observed. These changes, called single nucleotide polymorphisms (SNP) are present in 1-5% of the population. MATERIAL AND METHODS: A total of 92 subjects were recruited, including 28 centenarians and 64 controls, in order to find SNP that maybe implicated in the extreme longevity, as in the centenarians. Blood samples were collected to isolate and amplify the DNA in order to perform the analysis of SPN by Axiom™ Genotyping of Affymetrix technology. Statistical analyses were performed using the Plink program and libraries SNPassoc and skatMeta. RESULTS: Our results show 12 mutations with a p<.001, where 5 of these (DACH1, LOC91948, BTB16, NFIL3 y HDAC4) have regulatory functions of the expressions of others genes. CONCLUSIONS: Therefore, these results suggest that the genetic variation between centenarians and controls occurs in five genes that are involved in the regulation of gene expression to adapt to environmental changes better than controls.